Benzimidazole nucleosides are particularly attractive as potential antiviral agents because of their ability to avoid some major pathways of bioactive purine (bicyclic) nucleoside inactivation, e.g., deamination by adenosine deaminase and glycosidic bond cleavage by purine nucleoside phosphorylases. For example, current therapy for HCMV includes the use of drugs such as ganciclovir (also known as DHPG), foscanet, and cidofovir. However, known benzimidazole nucleosides such as 5,6-dichloro-1-(.beta.-D-ribofuranosyl) benzimidazole (DRB) have demonstrated only marginal levels of activity or generally unacceptable levels of cytotoxicity, or both, thereby greatly diminishing their usefulness in the treatment of viral infections. Recently, benzimidazole compounds, such as TCRB (2,5,6-trichloro-1-(2'-.beta.-D-ribofuranosyl)-benzimidazole) and BDCRB (2-bromo-5,6-dichloro-1-(2'-.beta.-D-ribofuranosyl)-benzimidazole) have also been found to be useful against HCMV infections. See, for example, Townsend et al., J. Med. Chem., Vol. 38, pp. 4098-4105 (1995).
A number of benzimidazole nucleosides have been synthesized and tested for their antiviral activity and cytotoxicity in an effort to identify a compound with superior anti-human cytomegalovirus (HCMV) activity to ganciclovir and foscamet. Antiviral activity of polysubstituted benzimidazoles such as 5,6-dichloro-1-(-.beta.-D-ribofuranosyl)benzimidazole (DRB) and some closely related derivatives have been previously described (I. Tamm, Science (1954) Vol. 120:847-848). Their activity against specific viruses, such as RNA rhinovirus and DNA herpes simplex virus type 1 and type 2, also has been reported.
Several of the 5'-deoxyribosyl benzimidazole analogs, including 2,5,6-trichloro-1-(-.beta.-D-ribofuranosyl)benzimidazole (TCRB) have shown very potent activity against HCMV and low cellular toxicity at concentrations inhibiting viral growth. Structural activity relationships of TCRB and heterocycle and carbohydrate modified derivatives have been reported. (See, Revenkar, R. G. and Townsend, L. B. (1968) J. Heterocyclic Chem. Vol. 5:477-483; Townsend, L. B. and Drach, J. C., Fifth International Conference on Antiviral Research Vancouver, British Columbia, March 1992; Revenkar, R. G. and Townsend, L. B. (1968) J. Heterocvclic Chem. Vol. 5:615-620; Zou, R. et al. "Design, synthesis and antiviral evaluation of some TCRB analogs modified on the benzene moiety" Poster #142. Division of Medicinal Chemistry, 204th American Chemical Society National Meeting, Washington, D. C., Aug. 23-28, 1992; and Saluja, S. et al. "Synthesis and antiviral activity of certain 2-substituted-5,6-dichlorobenzimidazole acyclic nucleosides. Poster #146. Division of Medicinal Chemistry, 204th American Chemical Society National Meeting, Washington, D. C., Aug. 23-28, 1992.)
The present invention pertains to imidazo[1,2-a]pyridines, which are structurally analogous to benzimidazoles, as illustrated below. The imidazo[1,2-a]pyridines of the present invention have been shown to have antiviral activity and low cytotoxicity. ##STR2##
Throughout this application, various publications, patents, and published patent applications are referred to by an identifying citation. The disclosures of the publications, patents, and published patent specifications referenced in this application are hereby incorporated by reference into the present disclosure to more fully describe the state of the art to which this invention pertains.